The Steroid Hormone 20-Hydroxyecdysone Up-regulates Ste-20 Family Serine/Threonine Kinase Hippo to Induce Programmed Cell Death.

The steroid hormone 20-hydroxyecdysone (20E) and the serine/threonine Ste20-like kinase Hippo signal promote programmed cell death (PCD) during development, although the interaction between them remains unclear. Here, we present evidence that 20E up-regulates Hippo to induce PCD during the metamorphic development of insects. We found that Hippo is involved in 20E-induced metamorphosis via promoting the phosphorylation and cytoplasmic retention of Yorkie (Yki), causing suppressed expression of the inhibitor of apoptosis (IAP), thereby releasing its inhibitory effect on caspase. Furthermore, we show that 20E induced the expression of Hippo at the transcriptional level through the ecdysone receptor (EcR), ultraspiracle protein (USP), and hormone receptor 3 (HR3). We also found that Hippo suppresses the binding of Yki complex to the HR3 promoter. In summary, 20E up-regulates the transcription of Hippo via EcRB1, USP1, and HR3 to induce PCD, and Hippo has negative feedback effects on HR3 expression. These two signaling pathways coordinate PCD during insect metamorphosis.